Menstrual disorders affect the lives of millions of women. Painful menstrual periods associated with heavy menstrual bleeding often require medical attention and initiation of appropriate therapy.
Painful menstrual periods may be clinically diagnosed as primary or secondary dysmenorrhea. Primary dysmenorrhea is defined as painful menstrual periods in women with normal pelvic anatomy. It is characterized by crampy pelvic pain beginning shortly before or at the onset of menstrual periods and lasting one to three days. Dysmenorrhea also may be secondary to pelvic organ pathology.1 Reported dysmenorrhea prevalence rates range from 43% to 90%. The variability of these estimates is explained by differences in the methods of data collection, the definitions of dysmenorrhea and populations studied2.
Heavy menstrual bleeding is defined as menorrhagia when the menstrual blood loss (MBL) exceeds 80 mL per menstrual cycle. In real-world practice, if a woman's periods are so heavy or so long that she finds them distressing, then she is experiencing heavy menstrual bleeding. One-third of all women report heavy menstrual bleeding at some point in their lives, and in Western countries about 5% of reproductive-aged women seek treatment for it annually3.
With the high prevalence of dysmenorrhea and menorrhagia, one may expect that a substantial number of women suffer from both diseases concomitantly. Days of painful menstrual periods in conjunction with excessive MBL may also be experienced by women not clinically diagnosed with either condition, or diagnosed with only one of them (e.g., clinically diagnosed menorrhagia in the absence of dysmenorrhea; or clinically diagnosed dysmenorrhea in the absence of menorrhagia).
In North America and Europe, dysmenorrhea and menorrhagia are often treated by off-label use of approved hormonal contraceptives. For a number of women, the treatments may not be acceptable due to known contraindications, hormone-related adverse events and/or undesirable changes in the menstrual bleeding pattern, including unpredictable intra-cyclic bleeding, irregular menstrual periods and/or the development of amenorrhea4,5,6 Due to known safety issues, danazol is rarely considered as a viable pharmacological treatment option. Surgical removal of the uterus (i.e., hysterectomy) may be considered for women with severe, refractory dysmenorrhea and menorrhagia. Yet, this is a radical treatment option with known undesirable consequences, including loss of fertility, surgical morbidity, as well as entailing high cost. There is limited evidence supporting minimally invasive methods of endometrial destruction as efficacious treatment options for dysmenorrhea and menorrhagia1,7.
Non-steroidal anti-inflammatory drugs (NSAIDs) are currently considered the most appropriate initial therapy for dysmenorrhea.1,8,9,10,11,12,13,14,15,16 The following NSAIDs are commonly prescribed for the treatment of pain associated with dysmenorrhea: (1) Mefenamic acid, (Ponstel®); (2) Ibuprofen (Motrin®, Advil®); (3) Diclofenac potassium (Cataflam®); (4) Naproxen sodium (ANAPROX®/ANAPROX® DS); (5) Ketoprofen (Orudis®); (6) Meclofenamate sodium.17,18,19,20,21,22,23 Ibuprofen, naproxen and ketoprofen are recommended drugs.11,12 In the published meta-analysis, ibuprofen was singled out as the drug having the most favorable risk-benefit ratio.16 
Oral NSAIDs have been shown to reduce MBL.6,25,26 The NSAIDs' ability to reduce MBL is related to the established relationship of endomyometrial prostaglandins to the genesis of menorrhagia. The most extensively studied NSAIDs, the fenamates, inhibit prostaglandin synthesis and bind to prostaglandin receptors which are significantly increased in women with menorrhagia.24 
However, many patients desire greater reduction of the amount of menstrual flow than what is typically achievable using recommended doses of oral NSAIDs.29 To ensure greater reduction of MBL, the maximal NSAID doses must often be administered.4 This leads to undesirable side effects such as diarrhea, nausea, vomiting, stomach pain, constipation, and allergic reactions and is not optimal, particularly if a much lower NSAID dose is sufficient to alleviate menstrual pain. As an example, a high dose of ibuprofen (800 mg every 8 hours) has been recommended for MBL reductions, while a lower dose (400 mg every 4 hours as necessary for pain relief19) may be sufficient to alleviate menstrual pain. A recommendation in the FDA-approved class labeling for NSAIDs is to use the lowest effective dose for the shortest duration possible.21 
In addition, NSAIDs demonstrate inferior efficacy in reducing MBL when compared to another drug widely used for treatment of menorrhagia, oral tranexamic acid. Oral tranexamic acid is marketed in the U.S. as Lysteda® and both within and outside the U.S. as Cyklokapron®. As is reported in the Lysteda label, tranexamic acid is a synthetic lysine amino acid derivative which diminishes the dissolution of hemostatic fibrin by plasmin. In the presence of tranexamic acid, the lysine receptor binding sites of plasmin for fibrin are occupied, preventing binding to fibrin monomers, thus preserving and stabilizing fibrin's matrix structure.32 The antifibrinolytic activity of tranexamic acid results in inhibition of the dissolution of clots.28 For many women, oral tranexamic acid is an efficacious treatment option. Clinical studies indicated that a 3900 mg/day regimen (marketed in the US as Lysteda) meets MBL reduction targets established by the FDA and significantly reduces limitations on social, leisure and physical activities.32,36 
However, the treatment-induced changes in MBL established in the Lysteda clinical trials may be not satisfactory for some women, and many patients may desire even greater reduction of the amount of menstrual flow. As was noted in the medical review of the Lysteda NDA, less than half (44%) of subjects returned to normal MBL after treatment (i.e., achieved a mean on-treatment MBL of less than 80 mL). There were no statistically significant differences between tranexamic acid and placebo treatment with regard to reduction of large stains, small and large clots as well as for changes in serum ferritin levels.36 The latter endpoint is particularly meaningful for women with impaired iron status and/or clinically-diagnosed anemia frequently associated with menorrhagia.
In the evaluation of tranexamic acid in the treatment of menorrhagia performed in 2000 by the European Agency for the Evaluation of Medicinal Products (EMEA), a dose-dependent increase in efficacy was noted. The same review recommended a daily dose of 3-4 g/day and indicated that the risk of gastrointestinal adverse events is increased at 6 g/day.34 While the FDA-approved Lysteda regimen (up to 3.9 g/day) is within the aforementioned recommended dosing range, certain Warnings and Precautions, including dose adjustment in women with renal impairment; increase in the risk of blood clots, stroke, or myocardial infarction in the event of concomitant therapy with hormonal contraceptives; the possibility of severe allergic reactions; and visual or ocular adverse effects,6 reflect regulatory concerns regarding Lysteda's safety. In the risk-benefit assessment, the FDA medical reviewer suggested a 50% dose reduction for women who do not tolerate the common adverse events associated with the approved treatment regimen.36 
A possibility of combining oral NSAID and oral tranexamic acid treatments has been suggested.6 It may be assumed that the currently-approved doses of 3.9 mg/day for Lysteda (US) and 3.0 mg/day for Cyklokapron® (ex-US) would be used.27,29 A combination oral tablet containing the standard doses of tranexamic acid (500 mg) and NSAID mefenamic acid (250 mg) is marketed in India (under Gynameno-Plus® and other trade names). For the treatment of primary dysmenorrhea, the mefenamic acid (Ponstel®) label recommends 500 mg as an initial dose followed by 250 mg every 6 hours, starting with the onset of bleeding and associated symptoms.17 To comply with this recommendation, five Gynameno-Plus tablets must be taken daily. Therefore, the daily dose of co-administered tranexamic acid would be 2500 mg (i.e. 65% and 85% of Lysteda and Cyklokapron approved doses, respectively). These treatment modalities do not take into consideration the substantial contribution of the NSAID component to the MBL reduction. As a result, they use doses of tranexamic acid which are much greater than needed for adequate control of excessive MBL resulting in increased incidence of adverse events.
Taken together, the clinical evidence indicates that the efficacy of oral NSAIDs in the treatment of dysmenorrhea accompanied with heavy menstrual bleeding cannot ensure adequate reduction of MBL. Due to safety issues reflected in relevant FDA guidance, an increase in an NSAID dose cannot be considered as an acceptable option. The efficacy of oral tranexamic acid in the reduction of MBL must also be weighed against the potentially disturbing side effects associated with this medication. When administered concomitantly via the conventional oral route at approved doses, the combination of an NSAID and tranexamic acid may raise safety concerns.